PROJECT SUMMARY/ABSTRACT Polychlorinated biphenyls (PCBs) remain a significant children?s health concern because they continue to contaminate food and indoor air, especially in schools across the United States. Non-dioxin-like (NDL) PCBs are implicated as environmental risk factors for neurodevelopmental disorders, and the parent grant addresses the critical need to understand the mechanisms by which NDL PCBs interact with genetic susceptibility factors to influence risk for developing these disorders. The long-term goal is to identify and understand factors that influence individual susceptibility to environmentally-mediated childhood disorders and, ultimately, to reduce the burden of these disorders to individuals and society. The objective of the proposed transdisciplinary and translational studies is to expand the scope of the current project to investigate a PCB congener (PCB 11), route of exposure (inhalation) and target organ (developing lung) not addressed in the parent grant. Additionally, this project will employ state-of-the art optogenetic techniques to translate in vitro observations of PCB effects on structural connectivity to functional connectivity in living animals. The consortium enables extensive collaborations among the PIs, including sharing of animal models, unique skills (optogenetics) and expertise (PCB toxicity, inhalation exposure, biodistribution, in vivo imaging). The Specific Aims are to: (1) Test the hypothesis that the disposition and neurotoxicity of PCB 11 differs when maternal exposure occurs via the diet versus inhalation; (2) Use optogenetics to test the hypothesis that developmental exposure to PCB 11 alters sensorimotor learning coincident with changes in neural assemblies and patterns of synaptic connectivity in vivo; and (3) Test the hypothesis that exposure to PCB 11 alters conducting airway epithelial development, airway innervation and airway oxidant stress/responsiveness and that the response is influenced by route of exposure. Aim 1 will fill a data gap on how the route of exposure influences PCB developmental neurotoxicity. Aim 2 will determine whether PCB-induced changes in structural connectivity of primary cultured neurons translate to changes in functional connectivity in the intact living brain that impair behavior. Aim 3 will determine whether PCB 11 interferes with the innervation and function of the developing lung, an understudied target in PCB toxicity. All three aims will generate novel toxicity data for PCB 11, a congener emerging as a prevalent PCB contaminant in complex environmental mixtures, including air and the serum of women at risk for having a child with a NDD. The proposed research is innovative because it uses state-of-the-art methods to: characterize how the route of PCB exposure affects developmental toxicity; confirm that in vitro observations of PCB effects on structural connectivity can be translated to physiological consequences in vivo; and evaluate the developing lung as a target organ for PCBs. These outcomes are significant because they will inform risk assessment for PCB 11, a prevalent environmental contaminant for which there is little toxicity data.